This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by degeneration of dopaminergic neurons located within the substantia nigra, pars compacta (SNc). Chronic deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus pars internus (GPi) has proven to be an effective therapy for the treatment of this disorder producing substantial improvements in tremor, bradykinesia, and rigidity, but has been less effective on improving gait and postural stability. Although there has been some recent exploration of the pedunculopontine nucleus (PPN) as a target for stimulation for the treatment of gait and balance problems in PD patients, the data are thus far extremely limited and highly controversial. The controversy stems in part from limitations associated with previous studies of PPN stimulation in non-human primates (NHP) as well as humans with PD. Few studies have systematically evaluated the effect of PPN stimulation on PD motor symptoms with confirmation of lead location within the PPN, either via postoperative imaging or postmortem studies in humans or histological confirmation in primate studies. Moreover, the primate studies performed to date have not quantitatively evaluated the effect of PPN stimulation on gait, while the data from human studies have been contradictory. These limitations make it difficult to determine whether the observed effect, or lack thereof, are indeed due to stimulation in the PPN. Although the PPN is considered a potentially effective target for the improvement of gait and balance in idiopathic PD, these limitations have led some to question its efficacy, while others rush to implant leads in patients before establishing physiological guidelines to identify the PPN and allow for accurate lead placement. To address these limitations we propose to: 1) characterize the electrophysiological features of neuronal activity in the PPN before and after MPTP administration in the parkinsonian primate model;and 2) implant and subsequently assess, using objective, quantitative measures, the effect of PPN DBS on gait in the MPTP NHP model of PD as the animal ambulates briskly on a treadmill. Histological confirmation of lead location will be performed following the assessments. The effect of PPN DBS on other motor signs of PD including bradykinesia/akinesia and rigidity will also be assessed in this study. We hypothesize that PPN neurons will exhibit a decreased mean discharge rate and increased bursting in the PD state secondary to increased inhibitory output from the internal segment of the globus pallidus (GPi) to the PPN. We also hypothesize that PPN DBS will be associated with a frequency dependent improvement in motor behavior, with low frequency stimulation patterns (i.e., 5 - 50 Hz) improving gait, akinesia and rigidity, while higher frequencies will exacerbate them. PUBLIC HEALTH RELEVANCE: This proposal addresses Challenge Area 15: Translational Science, and Specific Challenge Topic: Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease: 15-NS-103. The goal of this study is to determine whether electrical stimulation of certain brain regions can be used to improve the gait and balance instabilities associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of deep brain stimulation (DBS) of the brainstem pedunculopontine nucleus (PPN) on gait dysfunction. The PPN is considered a potentially effective target for the improvement of gait and balance in PD by a number of preliminary studies. However, these studies have several limitations, leading some to question its efficacy, while others rush to stimulate PPN in patients before sufficient guidelines are established for accurate localization of this target. To addresses these limitations, this study will characterize the changes in neuronal activity that take place in the PPN following development of PD, help determine physiological guidelines that can be used to identify the PPN for lead placement, and quantitatively characterize the effect of PPN DBS on PD motor symptoms. This study will determine whether or not PPN DBS can be effective in treating these motor signs and provide a rationale-based approach to the development of future clinical trials of PPN DBS for the treatment of PD symptoms. As a treatment of gait dysfunction, the utility of PPN DBS may extend beyond the PD population to other movement disorders, including progressive supranuclear palsy and multiple systems atrophy.